Compelling evidence suggest that the initial phases of the atherosclerosis may be hemangiogenesis dependent. However, the mechanism(s) whereby hematopoiesis and angiogenesis may contribute to atheroma formation are not known. We have shown that bone marrow (BM)-derived endothelial and hematopoietic precursor ceils may play an essential role in supporting post-natal angiogenesis. The main aim of this proposal is to define the physiological contribution of BM-derived hematopoietic and vascular progenitors to atheroma formation. We have identified a population of circulating VEGFR2+ (KDR, Flk1) endothelial cells (CEPs) that have the capacity to be recruited from BM to the angiogenic vascular bed (i.e. proliferating atheromas). Signaling through VEGFR2 is the critical for the proliferation, survival and differentiation of CEPs. We have also discovered that VEGFR1 (FLt-1) is expressed on hematopoietic precursor cells (HPCs) including myelomonocytic precursor cells as well as precursor cells resembling smooth muscle cells (SMPs). VEGFR2+ CEPs and VEGFR1+ HPCs can be co-mobilized and co-recruited to the atheromas in apoE deficient mice. Mobilization of the progenitors is dependent on the metalloproteinase activation (MMP-9) and release of stem cell active cytokines. These data suggest that angiogenic factors, such as VEGF, released within the atheromas, promote recruitment of BM precursor cells, thereby enhancing atherosclerotic process. Based on these studies, we hypothesize that atheromas provide a prohemangiogenic microenvironment that is permissive for recruitment of BM-derived cells. Angiogenic factors promote mobilization, recruitment, and incorporation of BM-derived VEGFR2+ CEPs, and VEGFR1+ HPCs, including myelomonocytic cells, to the atherosclerotic lesions. We propose that signaling through VEGFR1 contributes to recruitment of myelomonocytic cells and foam cell generation, thereby enhancing atheroma formation. Inhibition of VEGFR2 and or VEGFR1 signaling may inhibit initial phases of atheroma formation and diminish the development of atherosclerotic vascular lesions that are prone to hemorrhagic rupture. Identifying factors that inhibit VEGFR2 or VEGFR1 signaling may provide a novel mechanism to inhibit atheroclerosis. These goals will be pursued through the following specific aims. 1) Determine temporal, spatial and regional expression of VEGFR2 and VEGFR1 on pre-existing endothelial and recruited BM-derived CEPs, HPCs, and SMP during atheroma formation in apoE -/- and LDLr -/- mice, MMP9-/+ apoE -/-, PIGF-/- apoE -/-, and Id1+/- Id3-/- apoE-/- mice. 2) Define the role of VEGFR2 and VEGFR1 signaling in the regulation of mobilization, survival and recruitment of CEPs, and HPCs to the atheromas. 3) Evaluate the efficacy of inhibiting VEGFR2 and VEGFR1 signaling in blocking atheroma formation in the apoE-/- and LDLr-/- knock out mice. Inhibition of VEGFR2 and VEGFR1 signaling may inhibit initial phases of atheroma formation and diminish atherosclerosis.